Pain is a tremendous human health problem, representing the primary symptom that motivates people to seek medical attention and accounting for considerable morbidity and even mortality. The expression of pain us subject to large individual difference; even after presumable similar injuries some people report pain whereas others are pain-free. In addition, responses to analgesic (i.e., pain-inhibiting) drugs are quite variable. Accordingly, a number of genetic animal models of analgesic sensitivity have been identified or developed, and much is now known about the genetic mediation of analgesic sensitivity, including the location of genes influencing this trait. In contrast, almost nothing is known about a related and conceptually more basic issue, the genetic mediation of sensitivity to pain itself. To full understand the mechanism of action of analgesic drugs, one must first understand mechanisms underlying pain transmission and modulation. We have identified two inbred mouse strains that are highly sensitive to, and highly resistant to, pain as measured on a number of standard assays. The most robust stain difference is seen on the "tonic phase"of the formalin test, an assay of inflammatory pain that has received considerable attention in recent years. The present proposal has two main aims. First, we will endeavor to localize chromosomal regions containing genes that are associated with variability in pain sensitivity, using a technique known as quantitative trait locus (QTL) mapping. Due to the extensive linkage homology that exists between the mouse and human genomes, mapped QTLs in the mouse are likely to immediately suggest chromosomal regions for QTLs in humans. The second major aim of this proposal is to use artificial selection to produce mice displaying high and low tonic phase formalin pain behavior. Such seletected mouse lines would represent the first direct genetic model of pain sensitivity. We will use these selected lines to assess possible genetic correlations with opioid analgesic magnitude, non-opioid analgesic magnitude, sensitivity to inflammation-induced hyperalgesia, and susceptibility to neuropathic pain. Possible clinical applications of this work might include the development of a pre-operative blood test that would predict post-operative analgesic requirements, the development of novel analgesic strategies, and gene therapy for chronic pain sufferers refractory to conventional treatment.